Dry eye, also known as conjunctivitis sicca or keratoconjunctivitis sicca, is a common ophthalmological disorder involving breakdown of the pre-ocular tear film, resulting in dehydration of the exposed outer surface of the eye.
Atopic keratoconjunctivitis involves inflammation of the conjunctiva and cornea characterized by intensely itchy red areas on the eyelids, a discharge, or scaly and crusty eyelids. The eyes may become sensitive to light and the eyelids may noticeably thicken. Permanent scarring of the cornea may occur due to rubbing and scratching of the eyes resulting in visual changes.
Vernal keratoconjunctivitis can occur under dry, dusty, windy, and warm weather conditions. Eyes can become intensely itchy, sensitive to light, and can produce a stringy discharge; eyelids may feel uncomfortable and droopy. An examination of the eye reveals severe inflammation due to a vast number of mast cells and accumulated eosinophils.
In giant papillary conjunctivitis, large papillae, or bumps, develop on the conjunctiva under the upper eyelid. Redness and itching of the eye develop along with a thick discharge due to irritation from a foreign substance.
To date, dry eye has been treated with topical administration of artificial tear solutions. Some of these solutions contain mucomimetic substances to temporarily replace or replenish the mucin layer in mucin deficient patients. Use of methylprednisolone has been proposed in a short-term “pulse” treatment to treat exacerbations of dry eye. The proposed “pulse” therapy is required to avoid complications associated with traditional steroid therapy for inflammatory conditions such as increased intraocular pressure and cataract formation.
Inflammation is generally treated with a standard anti-inflammatory regimen that includes steroids and/or non-steroidal anti-inflammatory drugs. These classes of drugs have potential side effects including intraocular pressure increase, cataract, glaucoma or corneal melting.
Vernal keratoconjunctivitis, giant papillary conjunctivitis and atopic keratoconjunctivitis have historically been treated with a regimen of oral or topical antihistamine and/or oral or topical steroid. Systemic treatment typically requires higher concentrations of the drug compound to be administered to afford an effective concentration to reach the necessary treatment site. Antihistamine compounds are known to have CNS activity, which manifest in drowsiness and drying of mucus membranes. Steroid therapy also has side effects that include elevation of intraocular pressure.
Undesired activity of phosphodiesterase 4 is present in the above-cited types of ocular disorders. Cyclic adenosine monophosphate (cAMP) is a known anti-inflammatory second messenger. Elevated cAMP levels inhibit leukocyte function and suppress cytokine production in a variety of cells, thereby reducing inflammation. Further, cAMP has been shown to stimulate lacrimal gland secretion and increase tear volume (Gilbard J P, et al., IOVS 31(7):1381-8, 1990).
Phosphodiesterase type-IV (PDE4 or PDE-IV) is the predominant cyclic nucleotide hydrolyzing enzyme found in inflammatory leukocytes, such as mast cells, neutrophils, monocytes and T-lymphocytes. PDE4 catalyzes the hydrolysis of cAMP, thereby reducing intracellular levels thereof which results in increased inflammatory activity.
Since PDE4 activity controls the levels of cAMP in inflammatory cells, inhibitors of this enzyme have anti-inflammatory activity and are useful therapeutic agents in reducing inflammatory processes contributing to the manifestations of dry eye and conjunctivitis. Elevation of cAMP by inhibition of phosphodiesterase has been shown to increase goblet cell secretion of mucin, stimulate lacrimal gland secretion and promote fluid secretion by ocular surface cells. Existing small molecule PDE4 inhibitors have been shown to suppress expression of proinflammatory cytokines, to stimulate secretion of mucins in human ocular surface epithelial cells, and to have efficacy in allergic inflammation and in uveitis.
Small molecule PDE4 inhibitors are not particularly potent and require high concentrations of drug with the attendant topical formulation difficulties. Further, inhibitors of phosphodiesterases vary in selectivity and specificity for individual enzymes and therefore can possess diverse pharmacological and toxicological properties.
The present invention provides highly selective inhibitors of PDE4 isoforms with the primary biological effect being suppression of inflammation.